Milciclib, which may be referred herein to as Compound 1, or N,1,4,4-tetramethyl-8-((4-(4-methylpiperazin-1-yl)phenyl)amino)-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide, has the following structure:

Milciclib is a small molecule inhibitor of multiple CDKs, including CDK1, CDK2, CDK4, CDK5, CDK7, and CDK9, and TRKs (TPKA and TRKC), has shown efficacy in several preclinical tumor models (Albanese C et al. (2010) Mol Cancer Ther 9:2243-2254.). In a phase I study, oral treatment with milciclib was found to be well-tolerated and the drug showed promising clinical responses in patients with advanced solid malignancies such as in thymic carcinoma, pancreatic carcinoma and colon cancer (Weiss G J et al. (2013) Invest New Drugs 31:136-144.) The major toxicity profile consisted of tremors and gastrointestinal toxicity which was reversible upon treatment suspension. Results from this study recommended a RP2D of 150 mg/day.
Particularly, hepatocellular carcinoma (HCC) is an extremely complex multi-factorial condition associated with many confounding factors affecting disease course and patient prognosis. A broad range of mechanisms, including telomere dysfunction, activation of oncogenic pathways, abrogation of DNA damage checkpoints, activation of pro-inflammatory and metastatic pathways, and induction of the oxidative stress response. Thus, an effective therapy for HCC needs to control proliferation of hepatocytes and also suppress their metastatic potential. Milciclib, exhibiting broad-spectrum inhibitory activities against CDKs, effectively retards proliferation of cancer cells. Therefore, it is reasonable to propose that anticancer activity of milciclib may be potentiated by an inhibitor of tyrosine kinase to produce synergistic anti-tumorigenic activity.
There is a need for novel therapies by using milciclib in combination with a second anticancer drug or agent for the treatment of cancer. The present application addresses such a need.